There are two main problems in conventional chemotherapy. 1) Metastasis may result generating numerous new neoplasms that require repeated treatment and 2) multi-drug resistance may develop in cancer cells, rendering the drugs useless since they are effectively pumped out. Based on the over expression of certain cell-surface receptors in cancer cells relative to normal cells, targeted cancer therapy aims to address the first problem by delivering cytotoxic agents specifically to primary tumors and metastatic cells. However, there are few, if any, targeted delivery strategies that can overcome multi-drug resistance (MDR). MDR arises because of the over expression of trans-membrane pumps known as efflux transporters. Efflux transporters belong to the ATP-binding cassette (ABC) family of membrane proteins, which includes Pglycoprotein. When they are over expressed on a cancer cell, it gains capacity to pump a wide range of anti-cancer drugs out of the cytoplasm, hence the name multi-drug resistance. Many current chemotherapy drugs work by damaging DNA, and thus inhibiting replication of rapidly dividing cancer cells. Consequently, these drugs must concentrate in the nucleus for optimal function. For example, the drug DOX targets the site of topoisomerase II action.
Previously used delivery platforms include metallic nanoparticles, liposomes, viruses and polymeric drug delivery systems. Numerous virus vectors have been studied for cancer treatment, some with promising clinical results. However, the FDA has not approved any virus-based therapeutic agent due to concerns about toxicity that became apparent in the 1999 Gelsinger gene therapy accident. This incident raised concerns regarding the immune response to human adenoviral vectors. In addition to immunogenicity, Adenovirus must be genetically disabled for use as a drug or gene delivery platform. From a regulatory perspective, even the low probability event of Adenovirus recombination is sufficient to impede its development and use as a vector.
Plant viruses provide an alternative strategy for drug, and potentially gene, delivery. Preliminary research indicates that non-enveloped icosahedral viruses also have potential for targeted cell delivery as multifunctional nanoparticles. One of the best-characterized viruses for nanotechnology applications is Cowpea chlorotic mottle virus (CCMV) (X. X. Zhao, et al., Virology, 207:486-494 (1995); A. Zlotnick, et al., Virology, 277:450-456 (2000); L. O. Liepold, et al., Physical Biology, 2:S166-S172 (2005); F. D. Sikkema, et al., Organic & Biomolecular Chemistry, 5:54-57 (2007), which has the ability to assemble in vitro. Also, Cowpea mosaic virus (CPMV) has been investigated for use as a delivery agent (M. Manchester and P. Singh, Advanced Drug Delivery Reviews, 58:1505-1522 (2006); G. Basu, et al., Journal of Biological Inorganic Chemistry, 8:721-725 (2003); S. Sen Gupta, et al., Bioconjugate Chemistry, 16:1572-1579 (2005); P. Singh, et al., Drug Development Research, 67:23-41, (2006)). Expression of a peptide on the C-terminus (T. Joelson, et al, Journal of General Virology, 78:1213-1217 (1997)) and coat polymorphism studies (C. Hsu, et al., Virology, 349:222-229 (2006)) of Tomato bushy stunt virus (TBSV) demonstrates a genetic approach to preparation of targeting PVNs (E. Gillitzer, et al., Chemical Communications, 2390-2391 (2002)). These viruses have been proposed as a delivery platform based on their ease of modification, low toxicity, and lack of replication in humans.